Alleviate Withdrawal Symptoms Research Articles

Randomised controlled trial (RCT) of daily aerobic exercise for inpatient cannabis withdrawal: A study protocol

Background and aimsCannabis withdrawal is thought to be a major contributor to relapse to cannabis use and is now included in the DSM-5. Aerobic exercise relieves withdrawal symptoms from tobacco and other drugs, but has yet to be tested in cannabis users. MethodsA prospective, single blind, parallel-group RCT comparing daily aerobic exercise to a control stretching intervention. SettingA seven-day inpatient hospital admission, with follow-up at 28 days’ post-discharge. ParticipantsThe study population will be 80 cannabis dependent adults seeking assistance with cannabis withdrawal. Intervention and comparatorParticipants in the Intervention group will undergo 35 min of aerobic exercise daily, at 60% of their VO2 Max, on an exercise bicycle. The Control group will participate in a structured non-aerobic daily stretching routine for 35 min daily. Both groups receive treatment as usual in the withdrawal management unit of the hospital. MeasurementsThe primary outcome measure is the severity of cannabis withdrawal symptoms assessed daily using the Cannabis Withdrawal Scale and the Marijuana Cravings Questionnaire – pre and post exercise, across the week. Mechanisms by which exercise may affect cannabis withdrawal will be assessed by analysis of endogenous cannabinoids, and plasma and urine cannabinoid levels. DiscussionThis is the first RCT of aerobic exercise for cannabis dependence that has a valid control group to aid in interpretation of findings. Should the intervention prove effective, it would give empirical support to an inexpensive and accessible treatment approach for drug withdrawal management.

From hypomania to mania after correcting severe hypoglicemia: A case report to recall insulin shock therapy

IntroductionIn the early 20th century, shock therapies developed worldwide as the most effective means to treat severe mental illness. In 1927, Manfred Sakel introduced the newly discovered insulin as a means to treat opioid-addicted patients, by relieving withdrawal symptoms. After noticing that some psychotic patients notably recovered from their psychotic symptoms after accidental insulin comas, he extended this technique to schizophrenic patients, arguing that up to 70% of his patients improved with this therapy. Insulin shock therapy soon spread all-over the world and became one of the most important treatments for severe mental illness. Regardless of the high-rate complications, insulin shock therapy only declined after the introduction of anti-psychotic drugs.ObjectiveDescription of a clinical case.MethodsNon-systematic review of literature and case report.ResultsA 70-year-old female with type-1 bipolar disorder and type-2 diabetes was referred to a psychiatry emergency department (ED) for 2-week behavioral disorder, featuring restlessness, agitation, insomnia, verbiage and persecutory delusions. In the ED, she presented calm, cooperating, with a subtle humor elation and slight disinhibition. The speech was somewhat confusing, but with normal debit. Delusional thought or hallucinations were not evident. Severe hypoglycemia was first detected by capillary glucose measurement and confirmed by a blood test. After the blood glucose was corrected she became gradually more restless, talkative, disinhibited, with clear humor elation, compatible with a manic state.ConclusionWe discuss if this case might be explained by the severe hypoglycemia and its correction, linking it to insulin shock therapy, reviewing this procedure's history, controversies and current developments.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Insight into nicotine addiction

The emergence of the epidemic of nicotine addiction in India and other nations is a global public health tragedy of untoward proportions. Smoking or chewing tobacco can seriously affect general, as well as oral health. Smoking-caused disease is a consequence of exposure to toxins in tobacco smoke and addiction to nicotine is the proximate cause of these diseases. This article focuses on nicotine as a determinant of addiction to tobacco and the pharmacologic effects of nicotine that sustain cigarette smoking. The pharmacologic reasons for nicotine use are an enhancement of mood, either directly or through relief of withdrawal symptoms and augmentation of mental or physical functions. Tobacco cessation is necessary to reduce morbidity and mortality related to tobacco use. Strategies for tobacco cessation involves 5A's and 5R's approach and pharmacotherapy. Dental professionals play an important role in helping patients to quit tobacco at the community and national levels, to promote tobacco prevention and control nicotine addiction. Dentists are in a unique position to educate and motivate patients concerning the hazards of tobacco to their oral and systemic health, and to provide intervention programs as a part of routine patient care.

Management of Acute Alcohol Withdrawal Syndrome in Critically Ill Patients.

Approximately 16-31% of patients in the intensive care unit (ICU) have an alcohol use disorder and are at risk for developing alcohol withdrawal syndrome (AWS). Patients admitted to the ICU with AWS have an increased hospital and ICU length of stay, longer duration of mechanical ventilation, higher costs, and increased mortality compared with those admitted without an alcohol-related disorder. Despite the high prevalence of AWS among ICU patients, no guidelines for the recognition or management of AWS or delirium tremens in the critically ill currently exist, leading to tremendous variability in clinical practice. Goals of care should include immediate management of dehydration, nutritional deficits, and electrolyte derangements; relief of withdrawal symptoms; prevention of progression of symptoms; and treatment of comorbid illnesses. Symptom-triggered treatment of AWS with γ-aminobutyric acid receptor agonists is the cornerstone of therapy. Benzodiazepines (BZDs) are most studied and are often the preferred first-line agents due to their efficacy and safety profile. However, controversy still exists as to who should receive treatment, how to administer BZDs, and which BZD to use. Although most patients with AWS respond to usual doses of BZDs, ICU clinicians are challenged with managing BZD-resistant patients. Recent literature has shown that using an early multimodal approach to managing BZD-resistant patients appears beneficial in rapidly improving symptoms. This review highlights the results of recent promising studies published between 2011 and 2015 evaluating adjunctive therapies for BZD-resistant alcohol withdrawal such as antiepileptics, baclofen, dexmedetomidine, ethanol, ketamine, phenobarbital, propofol, and ketamine. We provide guidance on the places in therapy for select agents for management of critically ill patients in the presence of AWS.

Nicotine Replacement Therapy

Nicotine Replacement Therapy

Effect of Red Clover on CYP Expression: An Investigation of Herb-Drug Interaction at Molecular Level.

Hormone replacement therapy and selective estrogen receptor modulator are the most common therapy for women going through menopause. These therapies though popular fail to relieve withdrawal symptoms such as hot flashes, fatigue, leg cramps and nausea. This scenario necessitates to herbal preparations as alternative which may lead to simultaneous intake of herbal preparations, containing flavonoids, as well as Selective estrogen receptor modulator hence creating a phenomenon of herb drug interaction. Here we investigate the effect of red clover on steady state mRNA levels of rat cytochrome P 450 enzymes. Further, red clover's effect on cytochrome P 450's expression has been investigated when co-administered with tamoxifen and raloxifene. Exposure to red clover resulted in significant down regulation of all the cytochrome P 450 isoform mRNA except cytochrome P 450 2C13 and cytochrome P 450 3A2. When red clover is given in combination with tamoxifen or raloxifene altered level of cytochrome P 450 enzyme mRNA is observed. Present results suggest that herbal medical preparations such red clover has potential for herb drug interaction.

Evidence for an internet addiction disorder: internet exposure reinforces color preference in withdrawn problem users.

This study examined whether exposure to the Internet could create a preference for colors associated with visited Web sites and explored the possible relationship with self-reported problematic Internet use and Internet deprivation. 100 adult participants were divided into 2 groups; one was deprived access to the Internet for 4 hours, and the other was not. After this period, they were asked to choose a color and complete a series of psychometric questionnaires concerning mood (Positive and Negative Affect Schedule), anxiety (Spielberger State-Trait Anxiety Inventory), and depression (Beck Depression Inventory). They were then given a 15-minute exposure to the Internet, and the Web sites they visited were recorded. They were then asked to again choose a color, complete the same psychometric questionnaires, and complete the Internet Addiction Test. The study was conducted between November 2013 and April 2014. For Internet-deprived, but not nondeprived, subjects, a reduction of mood and increased anxiety was noted in the higher problematic Internet users following Web cessation. There was also a shift toward choosing the color most prominent on the visited Web sites in these participants. No shift in mood, or toward choosing the dominant Web site color, was seen in the lower problem users. These findings suggest that the Internet can serve as a negative reinforcer for behavior in higher problem users and that the reinforcement obtained from the alleviation of withdrawal symptoms becomes conditioned, with the color and appearance of the visited Web sites giving them a more positive value.

Neonatal Abstinence Syndrome: The Experience of Infant Massage.

Babies born to women who have used opioids during pregnancy frequently develop withdrawal symptoms following birth. Although a consistently used protocol is not available to treat these infants, interventions commonly used include a pharmacological regimen and supportive care such as swaddling, frequent feedings, decreased sensory stimulation, and protection from skin breakdown (Murphy-Oikonen, Montelpare, Bertoldo, Southon, & Persichino, 2012). A qualitative study was designed to better understand how infant massage might impact these babies' behavior and the mothers' relationship with their babies. Themes derived from the data include empowerment, enjoyment and bonding, and calm and comfort. The themes suggest that infant massage helps alleviate withdrawal symptoms in infants while fostering a connection between mother and child.

Twenty years of Internet addiction … Quo Vadis?

Byline: P. Dalal, Debasish. Basu "A person who never made a mistake never tried anything new." -Albert Einstein THE BEGINNING In 1995, when the New York based psychiatrist Dr. Ivan Goldberg posted a sincere-looking but satirical note on the online psychiatric bulletin board PsyCom.net (no longer available now) taking a dig at the rigid diagnostic criteria of the newly released 4 [sup]th edition of the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association (APA) by "creating" a fictitious disorder called Internet addiction disorder (IAD) and cooking up its "diagnostic criteria" as per DSM style for substance dependence, little did he know that he had opened the proverbial Pandora's box. [sup][1] He and his bulletin board were flooded with people narrating their tales of woe of "remaining caught in the Net" and seeking help for their condition. This was one condition he did not intend to create (he himself did not believe that there could be a true "addiction" to Internet but rather excessive or pathological use), but there it was whatever name you gave it! In 1995, a clinical psychology student Ms Kimberly Young, then in Rochester, USA, got interested in the psychological factors behind computer use and independently conceived of "addictive use of the Internet" as a pathological condition. [sup][2] It is interesting to hear of this story from the author herself 20 years later: "Internet addiction began as a pet project in a young researcher's one bedroom apartment in Rochester, New York. I was that young researcher. It was in 1995, and a friend of mine's husband was seemingly addicted to AOL Chat Rooms spending 40, 50, and 60 h online at a time when it was still $2.95/h to dial into the Internet. Not only did they suffer financial burdens but also their marriage ended in divorce when he met women in online chat rooms." [sup][3] The rest, as they say, is history, with her first illustrative case report published in 1996 having been cited 755 times, and her first definitive research article titled, "Internet addiction: Emergence of a new clinical disorder," published in 1998, having been cited a phenomenal 3144 times as on December 15, 2015! [sup][4] In 1995, a clinical psychologist Mark Griffiths, working at Nottingham Trent University, Nottingham, UK, who had been interested in research on gambling, computer use, and use of various machines or technology by humans in general for a few years at that time, published an article named, "Technological addictions." [sup][5] The next year, in 1996, he published on Internet addiction, conceptualized by him as a subset of the broader term technology addiction. [sup][6] This was the beginning, 20 years ago. As the freelance writer Michael OReilly, reporting in Canadian Medical Association Journal in 1996, (who, himself, interestingly, declared that "he may be at risk for developing IAD") titled his article as "Internet addiction: A new disorder enters the medical lexicon," where he mentioned Young's still unpublished research on Internet addiction. [sup][7] Truly, a PubMed search on "Internet addiction" pegs this short report as the very first article included in PubMed on the topic. The Accolades… Now, in 2015/6, as on December 15, 2015, there are 1561 articles cited in PubMed on "Internet addiction." What is more interesting is a look at the acceleration rate of publication. While there were only three articles in 1996, there were 32 in 2005, 275 in 2014, and 296 (and still counting) in 2015! Thus, while the growth rate of publications was not hugely impressive in the first decade of its life, Internet addiction is now a robust young adult in its postteen year with a sizeable growth spurt in its second decade. Not many "new" terms can boast of such growth in just 20 years in the PubMed! As an aside, it is to be noted that the term "Internet addiction" has many competing contenders; some of the important ones are pathological Internet use, problematic Internet use (PIU), compulsive Internet use, Internet use disorder (IUD), and pathological use of electronic media among others. …

"Sub is a weird drug:" A web-based study of lay attitudes about use of buprenorphine to self-treat opioid withdrawal symptoms.

Illicit use of buprenorphine has increased in the U.S., but our understanding of its use remains limited. This study aims to explore Web-forum discussions about the use of buprenorphine to self-treat opioid withdrawal symptoms. PREDOSE, a novel Semantic Web platform, was used to extract relevant posts from a Web-forum that allows free discussions on illicit drugs. First, we extract information about the total number of buprenorphine-related posts per year between 2005 and 2013. Second, PREDOSE was used to identify all posts that potentially contained discussions about buprenorphine and opioid withdrawal. A total number of 1,217 posts that contained these terms were extracted and entered into NVivo data base. A random sample of 404 (33%) posts was selected and content analyzed. Buprenorphine-related posts increased over time, peaking in 2011. The posts were about equally divided between those that expressed positive and negative views about the effectiveness of buprenorphine in relieving withdrawal symptoms. Web-forum participants emphasized that buprenorphine's effectiveness may become compromised because of the "size of a person habit," and/or when users repeatedly switch back and forth between buprenorphine and other illicit opioids. Most posts reported use of significantly lower amounts of buprenorphine (≤2 mg) than doses used in standard treatment. Concomitant use of other psychoactive substances was also commonly reported, which may present significant health risks. Our findings highlight the usefulness of Web-based data in drug abuse research and add new information about lay beliefs about buprenorphine that may help inform prevention and policy measures.

SY22-4 * BEHAVIORAL PHARMACOLOGICAL EFFECTS OF NICOTINE: ITS RELEVANCE TO SMOKING HABIT

The motivation for smoking is complex. We should think at least three factors: (1) primary reinforcing effect of nicotine, (2) alleviation of withdrawal symptoms, and (3) psychopharmacological effects on cognition and emotion. The third factor has been thought to be a mere sequel of the withdrawal symptom recovery. However the animal behavioral studies have shown this is not always the case. Nicotine has intrinsic behavioral effects. A well-known example is the facilitation effect on vigilance (sustained attention). We have also shown that nicotine attenuates short-term memory impairment induced by scopolamine in monkeys. Moreover, the anxiolytic effect and social interaction-facilitating effect by nicotine are also reported. The animal studies show that these effects are subtle and the effective dose range is narrow. Nevertheless, we should not underestimate these effects when considering about the motivation for smoking. Smokers learn the best way to get an optimal dose of nicotine on an optimal occasion by adjusting inhalation (puffing). It is probable that smokers perceive these effects as “beneficial”. Treatment for nicotine dependence should note that quitting from smoking may deprive these benefits.

Patterns of non-compliant buprenorphine, levomethadone, and methadone use among opioid dependent persons in treatment.

BackgroundThe non-compliant use of opioid substitution treatment (OST) medicines is widespread and well-documented. However, less is known about characteristics of non-compliant OST medicine use and the factors that predict it. The two main goals of this study are to compare characteristics of non-compliant levomethadone, methadone, and buprenorphine use and to explore factors that may differentially predict it among opioid dependent persons in treatment.MethodsData from 595 opioid dependent patients with non-compliant OST medicine use were analyzed. Characteristics of use between substances were compared using chi-squared tests and predictive factors were explored through multinomial logistic regressions.ResultsNon-compliant levomethadone and methadone use was characterized by more frequent parallel consumption of other psychoactive substances and intravenous use, whereas buprenorphine was more often procured without a prescription. Regarding predictive factors, methadone was perceived to relieve withdrawal symptoms better than buprenorphine and levomethadone was perceived as being better at modulating the effects of other substances and worst at enhancing mood.ConclusionsPatterns of non-compliant use differ according to OST medicine. These patterns are considered with the reduction of non-compliant use and the improvement of treatment in mind.

Comparison of cotinine levels in pregnant women while smoking and when using nicotine replacement therapy.

Background:Nicotine replacement therapy (NRT) helps smokers quit smoking, but trials indicate that there is no evidence that it is effective during pregnancy. As metabolism increases during pregnancy, NRT may deliver insufficient nicotine to alleviate withdrawal symptoms. There is mixed evidence as to what levels of cotinine are reached from nicotine exposure during pregnancy while using NRT compared with smoking.Methods:We analyzed data on 33 pregnant participants from the NRT arm of a randomized control trial who had stopped smoking and were still using 15mg/16hr nicotine patches 1 month after quitting. Salivary cotinine levels when smoking at baseline were compared with levels on NRT at 1 month using the Wilcoxon test.Results:Cotinine levels were a median of 98.5ng/ml while smoking and 62.8ng/ml while using NRT and remaining abstinent (p = .045). Participants with the highest cotinine measurements when smoking also tended to have the steepest reduction in cotinine levels while using NRT. This was most noticeable among participants with baseline cotinine levels more than 150ng/ml (n = 9) who had a greater reduction in median cotinine levels (median difference −134.8ng /ml [95% CI = −144.5 to −125.9]) than those with a baseline cotinine level under 150ng/ml (n = 24; median difference −27.9ng/ml [95% CI = −49.35 to −1.75]).Conclusions:In a pragmatic trial that replicated clinical practice, cotinine levels generated using NRT during pregnancy were lower than levels achieved from smoking. Although the sample size of this study was small, our findings are significant and are consistent with the hypothesis that NRT patches deliver an inadequate dose of nicotine to aid smoking cessation during pregnancy.

Suicidal Death by Nicotine Poisoning

Nicotine is a natural water-soluble alkaloid obtained from the dried leaves and stems of tobacco plants (Nicotiana tabacum and Nicotiana rustica), with amounts of 0.5%-8% by weight. Because this substance has an addictive potential, leaves or products of tobacco have been sold as snuff, chewing tobacco, cigarettes, cigars and pipe tobacco. Nicotine is also used for therapeutic purposes, such as, in aiding the relief of withdrawal symptoms after quitting smoking, in gums or patches containing nicotine, or in electronic cigarettes. However, nicotine is also highly toxic. So much so that they are being used as a pesticide. However, in this form it rarely leads to fatalities. Paralysis of the respiratory muscle or cardiovascular collapse is considered as the mechanism of sudden death. Nevertheless, nicotine poisoning cases have been rarely reported for the past 20 years. Here, we present a rare case of nicotine intoxication

Cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated alcohol-withdrawal syndrome.

Objectives:Benzodiazepines (BZDs) are the first-line drugs in alcohol-withdrawal syndrome (AWS). Baclofen, a gamma-aminobutyric acidB (GABAB) agonist, controls withdrawal symptoms without causing significant adverse effects. The objective of this study was to compare the cost-effectiveness of baclofen and chlordiazepoxide in the management of uncomplicated AWS.Materials and Methods:This was a randomized, open label, standard controlled, parallel group study of cost-effectiveness analysis (CEA) of baclofen and chlordiazepoxide in 60 participants with uncomplicated AWS. Clinical efficacy was measured by the Clinical Institute Withdrawal Assessment for alcohol (CIWA-Ar) scores. Lorazepam was used as supplement medication if withdrawal symptoms could not be controlled effectively by the study drugs alone. Both direct and indirect medical costs were considered and the CEA was analyzed in both patient's perspective and third-party perspective.Results:The average cost-effectiveness ratio (ACER) in patient's perspective of baclofen and chlordiazepoxide was Rs. 5,308.61 and Rs. 2,951.95 per symptom-free day, respectively. The ACER in third-party perspective of baclofen and chlordiazepoxide was Rs. 895.01 and Rs. 476.29 per symptom-free day, respectively. Participants on chlordiazepoxide had more number of symptom-free days when compared with the baclofen group on analysis by Mann-Whitney test (U = 253.50, P = 0.03).Conclusion:Both study drugs provided relief of withdrawal symptoms. Chlordiazepoxide was more cost-effective than baclofen. Baclofen was relatively less effective and more expensive than chlordiazepoxide.

Rhodiola rosea L. extract and its active compound salidroside antagonized both induction and reinstatement of nicotine place preference in mice

Conventional pharmacological treatments for drug addiction aim to reduce three most important aspects: withdrawal syndrome, craving, and relapse. Pharmacological treatments currently available for the treatment of tobacco smoking are able to alleviate withdrawal symptoms but are not sufficiently effective in reducing craving and rarely effective to prevent relapse. Rhodiola rosea L., a well-known traditional oriental medicine with anxiolytic, antidepressive, antistress, and adaptogenic properties, has been recently shown to be effective in the prevention and treatment of nicotine-withdrawal symptoms. The present study used the conditioned place preference (CPP) model to systematically investigate, in mice, the effects of a R. rosea L. extract (RHO) and its active compound salidroside (SDS), on the reinforcing properties of nicotine and their efficacy in the vulnerability to reinstatement. To study the effects on the rewarding properties of nicotine, RHO (10, 15, and 20mg/kg) and SDS (0.2mg/kg) were tested both in the acquisition and expression of CPP induced by nicotine injection (0.5mg/kg). Moreover, the efficacy of RHO and SDS in preventing relapse induced by nicotine priming (0.1mg/kg, s.c.) and by restraint stress was also evaluated. Results showed the ability of RHO and salidroside to significantly reduce the rewarding properties of nicotine at all doses tested. RHO and SDS also suppressed both priming- and stress-induced reinstatement of CPP. The present study showed the positive effects of R. rosea L. in reducing rewarding properties and preventing relapse to nicotine and evidenced the important role of salidroside in the effects of the extract.

Activation of GABAergic Neurons in the Interpeduncular Nucleus Triggers Physical Nicotine Withdrawal Symptoms

Chronic exposure to nicotine elicits physical dependence in smokers, yet the mechanism and neuroanatomical bases for withdrawal symptoms are unclear. As in humans, rodents undergo physical withdrawal symptoms after cessation from chronic nicotine characterized by increased scratching, head nods, and body shakes. Here we show that induction of physical nicotine withdrawal symptoms activates GABAergic neurons within the interpeduncular nucleus (IPN). Optical activation of IPN GABAergic neurons via light stimulation of channelrhodopsin elicited physical withdrawal symptoms in both nicotine-naive and chronic-nicotine-exposed mice. Dampening excitability of GABAergic neurons during nicotine withdrawal through IPN-selective infusion of an NMDA receptor antagonist or through blockade of IPN neurotransmission from the medial habenula reduced IPN neuronal activation and alleviated withdrawal symptoms. During chronic nicotine exposure, nicotinic acetylcholine receptors containing the β4 subunit were upregulated in somatostatin interneurons clustered in the dorsal region of the IPN. Blockade of these receptors induced withdrawal signs more dramatically in nicotine-dependent compared to nicotine-naive mice and activated nonsomatostatin neurons in the IPN. Together, our data indicate that therapeutic strategies to reduce IPN GABAergic neuron excitability during nicotine withdrawal, for example, by activating nicotinic receptors on somatostatin interneurons, may be beneficial for alleviating withdrawal symptoms and facilitating smoking cessation.

Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans

Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here, we used PET and [(11)C]-(+)-PHNO ([(11)C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [(11)C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [(11)C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [(11)C]-(+)-PHNO binding in D2 and D3-rich areas (-12.0 and -15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [(11)C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.

Neural Bases of Pharmacological Treatment of Nicotine Dependence - Insights from Functional Brain Imaging: A Systematic Review

Nicotine dependence is difficult to treat, and the biological mechanisms that are involved are not entirely clear. There is an urgent need to develop better drugs and more effective treatments for clinical practice. A critical step towards accelerating progress in medication development is to understand the neurobehavioral effects of pharmacotherapies on clinical characteristics associated with nicotine dependence. This review sought to summarize the functional magnetic resonance imaging (fMRI) literature on smoking cessation with the aim to better understand the neural processes underlying the effects of nicotinic and non-nicotinic pharmacological smoking cessation treatments on specific symptoms of nicotine dependence and withdrawal. We conducted a search in Pubmed, Web of Science and PsycINFO databases with the keywords 'fMRI' or 'functional magnetic resonance imaging' and 'tobacco' or 'nicotine' or 'smok*'. The date of the most recent search was May 2012. The original studies that were included were those of smokers or nicotine-dependent individuals, published in the English language, with pharmacological treatment for nicotine dependence and use of fMRI with blood oxygen level-dependent (BOLD) imaging or continuous arterial spin labelling (CASL). No date limit was applied. Two of the authors read the abstracts of all studies found in the search (n = 1,260). The inclusion and exclusion criteria were applied, and 1,224 articles were excluded. In a second step, the same authors read the remaining 36 studies. Nineteen of the 36 articles were excluded. The results were tabulated by the number of individuals and their mean age, the main sample characteristics, smoking status, study type and methodology, and the main fMRI findings. Seventeen original fMRI studies involving pharmacological treatment of smokers were selected. The anterior and posterior cingulate cortex, medial and lateral orbitofrontal cortex, ventral striatum, amygdala, thalamus and insula are heavily involved in the maintenance of smoking and nicotine withdrawal. The effects of varenicline and bupropion in alleviating withdrawal symptoms and decreasing smoking correlated with modulation of the activities of these areas. Nicotine replacement therapy seems to improve cognitive symptoms related to withdrawal especially by modulating activities of the default-network regions; however, nicotine replacement does not necessarily alter the activities of neural circuits, such as the cingulate cortices, that are associated with nicotine addiction. The risk of bias in individual studies, and across studies, was not assessed, and no method of handling data and combining results of studies was carried out. Most importantly, positron emission tomography (PET) studies were not included in this review. fMRI studies delineate brain systems that contribute to cognitive deficits and reactivity to stimuli that generate the desire to smoke. Nicotinic and non-nicotinic pharmacotherapy may reduce smoking via distinct neural mechanisms of action. These findings should contribute to the development of new medications and discovery of early markers of the therapeutic response of cigarette smokers.

Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum

It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings. To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum. Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n = 42 or 4 mg, n = 24) or placebo (n = 66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence. In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110) = 1.28, p = 0.20, η²(p)= 0.20] nor an effect of treatment [F(7,124) = 0.45, p = 0.87, η²(p)= 0.03]. There was an effect of time [F(21,110) = 11.59, p < 0.001, η²(p)= 0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence. Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms.